Substituent effects on microstructure and polymerization of polyalkylsilsesquioxanes.
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Journal Article↗
Biomedical subjects
J K Lee
Publications and source records attributed to J K Lee.
Sequence analysis of hemagglutinin and nucleoprotein genes of measles viruses isolated in Korea during the 2000 epidemic.
To characterize the genetic properties of currently circulating measles viruses in Korea, the complete nucleotide sequences of hemagglutinin (H) protein and nucleoprotein (N) genes of Korean viruses were analyzed. The entire genes of H and N were directly amplified by RT-PCR from each clinical specimen and sequenced. Sequence analyses of H and N genes indicated that all Korean viruses had a high degree of homology (>99.8%) when compared with each other. The Korean viruses differed from other wild-type viruses by as much as 6.8% in the H gene and 6.5% in the N gene at the nucleotide level. The deduced amino acid variability was up to 6.4% for the H protein and up to 6.5% for the N protein. Phylogenetic analyses of nucleotide sequences and deduced amino acid sequences of the H and N genes revealed that all Korean viruses were grouped into the clade H1.
Disease Outbreaks↗
The Schizosaccharomyces pombe origin recognition complex interacts with multiple AT-rich regions of the replication origin DNA by means of the AT-hook domains of the spOrc4 protein.
The interaction between an origin sequence and the origin recognition complex (ORC), which is highly conserved in eukaryotes, is critical for the initiation of DNA replication. In this report, we have examined the interaction between the Schizosaccharomyces pombe (sp) autonomously replicating sequence 1 (ars1) and the spORC. For this purpose, we have purified the spORC containing all six subunits, a six-subunit complex containing the N-terminal-deleted spOrc4 subunit (spORC(Delta N-Orc4)), and the spOrc4 subunit by using the baculovirus expression system. Wild-type spORC showed sequence-specific binding to ars1, and the spOrc4 protein alone showed the same DNA-binding properties as wild-type spORC. In contrast, the spORC(Delta N-Orc4) and the Delta N-spOrc4p alone did not bind significantly to ars1. These findings indicate that the N-terminal domain of the spOrc4 protein that contains multiple AT-hook motifs is essential for the ars1-binding activity. DNA-binding competition assays with fragments of ars1 and DNase I footprinting studies with full-length ars1 revealed that the spORC interacted with several AT-rich sequence regions of ars1. These DNA-binding properties of spORC correlate with the previously determined sequence requirements of the S. pombe ars1. These studies indicate that because of its unique Orc4 subunit, S. pombe uses a mechanism to recognize its origins different from that used by Saccharomyces cerevisiae.
AT Rich Sequence↗
Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review.
CONTEXT: Adverse drug reactions are a significant cause of morbidity and mortality. Although many adverse drug reactions are considered nonpreventable, recent developments suggest these reactions may be avoided through individualization of drug therapies based on genetic information, an application known as pharmacogenomics. OBJECTIVE: To evaluate the potential role of pharmacogenomics in reducing the incidence of adverse drug reactions. DATA SOURCES: MEDLINE English-language only searches for adverse drug reaction studies published between January 1995 and June 2000 and review articles of variant alleles of drug-metabolizing enzymes published between January 1997 and August 2000. We also used online resources, texts, and expert opinion. STUDY SELECTION: Detailed inclusion criteria were used to select studies. We included 18 of 333 adverse drug reaction studies and 22 of 61 variant allele review articles. DATA EXTRACTION: All the investigators reviewed and coded articles using standardized abstracting forms. DATA SYNTHESIS: We identified 27 drugs frequently cited in adverse drug reaction studies. Among these drugs, 59% are metabolized by at least 1 enzyme with a variant allele known to cause poor metabolism. Conversely, only 7% to 22% of randomly selected drugs are known to be metabolized by enzymes with this genetic variability (range, P =.006-P<.001). CONCLUSIONS: Our results suggest that drug therapy based on individuals' genetic makeups may result in a clinically important reduction in adverse outcomes. Our findings serve as a foundation for further research on how pharmacogenomics can reduce the incidence of adverse reactions and on the resulting clinical, societal, and economic implications.
Anticoagulants↗
The anionic oxy-Cope rearrangement: using chemical reactivity to reveal the facile isomerization of the parent substrates in the gas phase.
The rearrangements of 1,5-hexadiene-3-oxide and 3-methyl-1,5-hexadiene-3-oxide have been studied in the gas phase, using both Fourier transform mass spectrometry (FTMS) and the flowing afterglow (FA) technique. Gas-phase studies of ionic rearrangements can be limited by analysis techniques such as collision-induced dissociation, which have the potential of driving the rearrangement prior to fragmentation. In the studies reported here, we have utilized methanol-O-d, methyl nitrite, and dimethyl disulfide as chemical reactivity probes to discern whether rearrangement of either of the alkoxides to their corresponding enolates occurs. Of the three structural probe reagents, dimethyl disulfide has been found to be most ideal, since it reacts efficiently with both alkoxides and enolates to produce a unique product from each. On the basis of the reactions observed between dimethyl disulfide and anions generated from 1,5-hexadien-3-ol and 3-methyl-1,5-hexadien-3-ol, we have found that the gas-phase Cope rearrangement of both tertiary and secondary alkoxides occurs under both FTMS and FA conditions. Use of dimethyl disulfide in the FTMS and evaluation of ion residence time in the FA lead to the establishment of an upper limit on the Delta H(*) of the rearrangement of both the parent secondary and tertiary substrates as approximately 11 kcal mol(-1) at 298 K. This value is consistent with our B3LYP/6-31+G* prediction. The rearrangement is also faster in the gas phase than in solution, in accord with theoretical predictions.
Journal Article↗
Quantitative analysis of transforming growth factor-beta 1 in ligamentum flavum of lumbar spinal stenosis and disc herniation.
STUDY DESIGN: The concentration of transforming growth factor-beta 1 (TGF-beta1) was examined in the ligamentum flavum of lumbar spinal stenosis and disc herniation. OBJECTIVE: To investigate the role of TGF-beta1 on hypertrophy of the ligamentum flavum in lumbar spinal stenosis compared with that of lumbar disc herniation. SUMMARY OF BACKGROUND DATA: The hypertrophy of the ligamentum flavum is known to be related to degenerative changes that are secondary to the aging process or mechanical instability. However, there has been no study to investigate the effect of biochemical factors, such as growth factors, associated with hypertrophy of the ligamentum flavum. METHODS: The concentrations of TGF-beta1 were analyzed in the surgically obtained ligamentum flavum specimens from lumbar spinal stenosis (n = 10; mean age 62.8 years) and disc herniation (n = 10; mean age 35.6 years) by enzyme-linked immunosorbent assay. The localization of TGF-beta1 within the ligamentum flavum was determined using immunohistochemical study. The thickness of the ligamentum flavum was measured with axial T1-weighted magnetic resonance imaging. The biochemical and radiologic results were compared for these two conditions. RESULTS: The mean concentration of TGF-beta1 was 123.78 pg/100 microg protein (range 11-374 pg/100 microg protein) in lumbar spinal stenosis and 38.56 pg/100 microg protein (range 0-155 pg/100 microg protein) in lumbar disc herniation; the difference between lumbar spinal stenosis and disc herniation was statistically significant (P = 0.029). The mean thickness of the ligamentum flavum was 4.44 mm (range 3.4-5.4 mm) in lumbar spinal stenosis and 2.44 mm (range 1.8-4.0 mm) in lumbar disc herniation; the difference between lumbar spinal stenosis and disc herniation was statistically significant (P = 0.001). On immunohistochemical study TGF-beta1 was positively stained on the fibroblasts within the ligamentum flavum specimens. CONCLUSION: The current results suggest that higher expression of TGF-beta1 by fibroblasts might be related to the development of hypertrophy of the ligamentum flavum in lumbar spinal stenosis.
Aged↗
Delayed induction of p38 MAPKs in reactive astrocytes in the brain of mice after KA-induced seizure.
Activation of p38 mitogen-activated protein kinase (p38 MAPK) has been implicated in pathological changes in inflammatory and apoptotic processes in various cell types including neurons. Here we report the delayed induction of p38 MAPKs in the brain of mice following kainic acid (KA)-induced seizure. The immunoreactivities of p38alpha and p38beta MAPKs were markedly increased in the brain 4 days after KA administration, especially in the areas undergoing selective neuronal loss. In particular, p38beta was dramatically increased in reactive astrocytes of CA3 and CA1 regions of hippocampus with its enriched localization in the nucleus of astrocytes. The induction of p38beta was sustained for more than 10 days after KA-treatment. Pre-administration of the selective neuronal nitric oxide synthase (nNOS) inhibitor, 7-nitroindazole (7-NI), which suppressed the delayed neuronal death as well as astrogliosis in hippocampus of seizure-experienced animals, dramatically repressed the delayed induction of p38beta MAPK in astrocytes. The repression was reversed by the co-injection with L-arginine (L-arg), a substrate for NOS, which coincided with the aggravation of neuronal death. Together, these data suggested a role of p38 MAPK signal pathway in delayed neuronal death and/or in reactive gliosis in mice with KA-induced seizure.
Animals↗
Chemosensitivity prediction by transcriptional profiling.
In an effort to develop a genomics-based approach to the prediction of drug response, we have developed an algorithm for classification of cell line chemosensitivity based on gene expression profiles alone. Using oligonucleotide microarrays, the expression levels of 6,817 genes were measured in a panel of 60 human cancer cell lines (the NCI-60) for which the chemosensitivity profiles of thousands of chemical compounds have been determined. We sought to determine whether the gene expression signatures of untreated cells were sufficient for the prediction of chemosensitivity. Gene expression-based classifiers of sensitivity or resistance for 232 compounds were generated and then evaluated on independent sets of data. The classifiers were designed to be independent of the cells' tissue of origin. The accuracy of chemosensitivity prediction was considerably better than would be expected by chance. Eighty-eight of 232 expression-based classifiers performed accurately (with P < 0.05) on an independent test set, whereas only 12 of the 232 would be expected to do so by chance. These results suggest that at least for a subset of compounds genomic approaches to chemosensitivity prediction are feasible.
Drug Resistance, Neoplasm↗
Lanthanide triflate-catalyzed three component synthesis of alpha-amino phosphonates in ionic liquids. A catalyst reactivity and reusability study.
The catalyst reactivity and reusability for the lanthanide triflate-catalyzed three component synthesis of alpha-amino phosphonates have been examined in room temperature ionic liquids, [bmim][X], in which the catalytic activities were very dependent on the counter anion, X, as well as on the phosphorus nucleophile, and moreover, the catalyst immobilized in an ionic liquid was reused several times without any loss of activity.
Journal Article↗
Delayed induction of alpha B-crystallin in activated glia cells of hippocampus in kainic acid-treated mouse brain.
Small heat shock proteins have been implicated in playing a role in various cellular processes, including stress-induced cell death. In kainic acid (KA)-treated rat brain, the immunoreactivity of heat-shock protein 27 (HSP27) was markedly increased in glia cells of the limbic system. In the present study, we demonstrated that alpha B-crystallin, a member of the small heat-shock protein family, was strongly induced in reactive astrocytes in hippocampus after KA-induced seizure. The induction was localized mainly in the CA3 region of hippocampus, where massive neuronal loss occurred. We also demonstrated that the delayed induction of alpha B-crystallin and HSP27 immunoreactivities in the hippocampus of epileptic animals was repressed to the levels seen in control animals with preadministration of the selective nNOS inhibitor 7-nitroindazole (7-NI). This repression was reversed by coinjection of L-arginine, a substrate of NOS. Together, these data suggest a role for alpha B-crystallin and HSP27 in reactive gliosis and/or in delayed neuronal death proceeded after KA-induced seizure.
Animals↗
Differential effects of forskolin and phobol 12-myristate-13-acetate on the c-fos and c-jun mRNA expression in rat C6 glioma cells.
The effects of forskolin (FSK) and phobol 12-myristate-13-acetate (PMA) on c-fos and c-jun mRNA expressions in rat C6 glioma cells were studied. Both FSK and PMA increased the c-fos mRNA level. The C-jun mRNA level was decreased by FSK, whereas it was increased by PMA. The elevated c-fos mRNA level, induced by FSK or PMA, was significantly inhibited by dexamethasone (DEX). In contrast, DEX did not affect the FSK- and PMA-induced response of the c-jun mRNA level. Cycloheximide (CHX) caused a superinduction of the FSK- or PMA-induced c-fos mRNA level. Furthermore, CHX also potentiated the PMA-induced c-jun mRNA level. However, CHX did not affect the FSK-induced down-regulation of the c-jun mRNA level. When C6 glioma cells were incubated with PMA and FSK, the PMA-induced c-jun mRNA level was inhibited by FSK, whereas FSK did not affect the PMA-induced c-fos mRNA level. Our results suggest that the activations of PKA and PKC pathways have different roles in the regulation of the c-jun mRNA expression in rat C6 glioma cells. PKA activation can inhibit induction of the c-jun mRNA expression by PMA. In addition, DEX appears to have a selective inhibitory action against c-fos, but not c-jun, -mRNA expression that is regulated by PKA and PKC. On-going protein synthesis inhibition is required for the superinduction of the c-fos expression that is induced by PMA, or FSK and the PMA-induced c-jun mRNA level.
Animals↗
Induction of transplantable mouse renal cell cancers by streptozotocin: in vivo growth, metastases, and angiogenic phenotype.
Interleukin-2-based regimens of biological therapy have shown some clinical promise for the treatment of kidney cancer in humans, although the mechanisms responsible for tumor regression occurring in these patients remain unclear. Preclinical insight into these mechanisms is limited by a paucity of orthotopic animal models of kidney cancer. We have used streptozotocin, an antibiotic and diabetogenic nitrosamine compound derived from Streptomyces achromogenes to induce new kidney tumors in BALB/c mice. Single or multiple doses of streptozotocin induced kidney tumors in up to 25% of mice by 50-90 weeks of age, with up to 18% characterized as renal cell carcinomas (RCCs). Several transplantable lines were obtained from the RCCs, and one of these lines was subsequently cloned. The initial tumor isolates and sublines were histologically reconfirmed to be RCCs, and all grew progressively but slowly (mean survival times, 57 to >100 days) in vivo after intrarenal implant. None of the primary isolates or sublines revealed mutations in either the VHL or Ras genes, although karyotype analysis and chromosome painting revealed the consistent presence of a submetacentric chromosome resulting from the fusion of chromosomes 16 and 19. Biological characterization of these tumors revealed several features analogous to the growth of human kidney cancers, including a propensity for the formation of lung metastases and high vascularity. This hypervascularity is evident by both gross and microscopic analysis and correlates with the expression of several proangiogenic genes. Overall, the features of orthotopic transplantability, slower in vivo growth (relative to the rapid growth rates of other transplantable mouse kidney tumors), propensity for lung metastases, and hypervascularity may make these tumors valuable models for the study of new therapeutic strategies based on antineovascular agents and antitumor cytokines.
Animals↗
Lipopolysaccharide inhibits induction of long-term potentiation and depression in the rat hippocampal CA1 area.
We examined the effects of lipopolysaccharide, a bacterial endotoxin, on synaptic plasticity in the rat hippocampal CA1 area in vitro. Lipopolysaccharide suppressed the induction of long-term potentiation elicited by tetanic stimulation and long-term depression, elicited by low-frequency stimulation of Schaffer collateral-commissural fibres at 10 and 50 microg/ml, respectively. Lipid A (1 microg/ml), the biologically active component of lipopolysaccharide, mimicked the effects of 10 microg/ml lipopolysaccharide on long-term potentiation and depression. Nifedipine, an L-type voltage-sensitive Ca(2+) channel antagonist, did not influence the induction of long-term potentiation and depression, whereas a high concentration of extracellular calcium enabled long-term potentiation induction in the presence of 10 microg/ml lipopolysaccharide. The NMDA receptor antagonist D,L-2-amino-5-phosphonovaleric acid (APV, 50 microM), nifedipine (10 microM) or lipopolysaccharide (10 or 50 microg/ml) partially reduced the magnitude of tetraethylammonium-induced long-term potentiation. Nifedipine combined with lipopolysaccharide completely blocked tetraethylammonium-induced long-term potentiation. Whole-cell voltage clamp recordings showed that lipopolysaccharide suppressed NMDA receptor-mediated excitatory postsynaptic currents (EPSCs). Our results indicate that lipopolysaccharide acutely modifies synaptic plasticity by blocking Ca(2+) entry through NMDA receptors, suggesting a possible mechanism for the amnesic action of bacterial infection.
Animals↗
Possible roles of JNK pathway in the regulation of hippocampal proenkephalin and immediate early gene expression induced by kainic acid.
Mitogen-activated protein kinases (MAPKs) may play crucial roles in the kainic acid (KA)-evoked excitotoxic effect and the regulation of transcription factors (e.g. c-Fos and c-Jun) in hippocampus, but their exact role in the regulation of KA-induced opioid peptides expression has not been well characterized in vivo. Therefore, we examined possible involvement of the phosphorylated form of JNK, as well as CREB, in the regulation of KA-induced proenkephalin and immediate early genes (IEGs) expression in the rat hippocampus. KA increased proenkephalin mRNA expression in rat hippocampus, which was decreased by pre-administration with cycloheximide (CHX, a protein synthesis inhibitor). KA alone increased c-fos as well as c-jun mRNA levels. CHX further enhanced KA-induced c-fos and c-jun mRNA levels. Additionally, KA increased the phosphorylation of JNK, especially JNK1, which was attenuated by CHX. CHX decreased KA-induced c-Fos protein expression. Interestingly, CHX itself increased the phosphorylation of CREB, which was abolished by KA administration. Our results suggest that the phosphorylation of JNK is involved in the up-regulation of the proenkephalin gene expression via c-Fos and c-Jun that is induced by KA in rat hippocampus. However, the phosphorylation of CREB is not associated with the up-regulation of the proenkephalin mRNA level induced by KA in the rat hippocampus.
Animals↗
Forskolin inhibits expression of inducible nitric oxide synthase mRNA via inhibiting the mitogen activated protein kinase in C6 cells.
This study has demonstrated the mechanism of protein kinase A (PKA)-dependent inhibition of astrocytic nitric oxide production and inducible NO synthase mRNA expression induced by lipopolysaccharide. In C6 glioma cells, the stimulation with lipopolysaccharide (LPS; 1 microg/ml) evoked increases of nitric oxide (NO) production, NO synthase (iNOS) mRNA expression, phosphorylation of p38 mitogen activated protein kinase (p-p38), and the activation of NF kappa B. LPS-induced NO production and iNOS mRNA expression were inhibited by the pretreatment with forskolin (FSK; 5 microM) in a dose-dependent manner, and which were reversed by PKA inhibition by compound H89. Furthermore, LPS-induced increases of p-p38, but not activation of NF kappa B, were also reduced by FSK and H89 reversed the FSK-induced inhibition response. The dose-dependent inhibition of NO production and iNOS mRNA expression by compound SB203580 (p38 inhibitor) suggests the participation of p38 in PKA-dependent inhibition of LPS-induced NO production and iNOS mRNA expression. However, the activation of NF kappa B by LPS also not affected by SB203580. Therefore, our results suggest that, in C6 glioma cells, LPS-induced NO production and iNOS gene expression may be regulated by PKA pathway through the reduction of activity of p38 kinase. This inhibitory role of PKA may not involve the activation of NF kappa B.
Animals↗
I(f) current and spontaneous activity in mouse embryonic ventricular myocytes.
Knowledge of the initiation of electrical and contractile activity in the embryonic heart relies to a large extent on data obtained in chicken. In recent years, molecular biological techniques have raised an interest in mouse physiology, including early embryonic development. We studied action potentials and the occurrence of one of the pacemaker currents, I(f), by the whole-cell voltage and current-clamp technique at the earliest stage at which a regular heartbeat is established (9.5 days postcoitum) and at 1 day before birth. We show, first, that at the early stage there is a prominent I(f) in mouse embryonic ventricles, which decreases by 82% before birth in concert with the loss of regular spontaneous activity of ventricular cells. Second, the decrease in I(f) current is associated with a slight change in channel gating kinetics and a decrease in total mRNA expression of the genes encoding for I(f) current. Third, the most prevalent mRNA subtype is switched from HCN4 to HCN2 during the second half of embryonic development. Fourth, the I(f) current may be modulated by the beta-adrenergic cascade, although the coupling to the beta-adrenoceptor in the sarcolemma itself is not yet mature. We conclude that I(f) current of the sinus node type is present in early embryonic mouse ventricular cells. In association with a loss of I(f) current, the ventricle tends to lose pacemaker potency during the second half of embryonic development.
Action Potentials↗
Primary hepatocytes from mice treated with IL-2/IL-12 produce T cell chemoattractant activity that is dependent on monokine induced by IFN-gamma (Mig) and chemokine responsive to gamma-2 (Crg-2).
The IFN-gamma-inducible proteins monokine induced by IFN-gamma (Mig) and chemokine responsive to gamma-2 (Crg-2) can contribute to IL-12-induced antiangiogenic and leukocyte-recruiting activities, but the extent to which leukocytes vs parenchymal cells in different organs contribute to the production of these molecules remains unclear. The results presented herein show that IFN-gamma-dependent induction of Mig and Crg-2 gene expression can occur in many nonlymphoid organs, and these genes are rapidly induced in purified hepatocytes isolated from mice treated with IL-2 plus IL-12, or from Hepa 1-6 hepatoma cells treated in vitro with IFN-gamma. In addition to depending on IFN-gamma, the ability of IL-12 or IL-2/IL-12 to induce Mig and Crg-2 gene expression in purified hepatocytes also is accompanied by the coordinate up-regulation of the IFN-gamma R alpha and beta-chains, in the absence of IL-12R components. Supernatants of primary hepatocytes obtained from mice treated in vivo with IL-2/IL-12 or from hepatocytes treated in vitro with IFN-gamma contain increased chemotactic activity for enriched human and mouse CD3(+) T cells, as well as mouse DX5(+) NK cells. The hepatocyte-derived chemotactic activity for mouse T cells but not NK cells was ablated by Abs specific for Mig and Crg-2. These results suggest that parenchymal cells in some organs may contribute substantially to initiation and/or amplification of inflammatory or antitumor responses.
Animals↗
Structure and expression of a CTP: phosphocholine cytidylyltransferase gene from Arabidopsis thaliana.
A genomic clone, which includes the CTP: phosphocholine cytidylyltransferase (CCT) open reading frame and its 5'- and 3'- flanking non-coding regions, has been isolated from Arabidopsis thaliana and sequenced. The CCT gene is approximately 3.0 kb in length and contains 8 exons interrupted by 7 introns, which range from 74 to 626 nucleotides. All nucleotide sequences for the intron 3' splice sites are consistent with the consensus AG sequence of plant pre-mRNA processing, while the major GT consensus sequence for the 5' splice site is conserved in 5 of 7 introns. Introns 5 and 6 have a minor GC consensus sequence instead. In the 5'-flanking region there are two sequences related to a cold-responsive element found in the cold-inducible promoter of the A. thaliana cor15a gene, plus one gibberellin-response element. The results from reverse transcriptase-PCR indicate that the expression of A. thaliana CCT is regulated by temperature. The expression level of CCT increased after a 30-min treatment at 5 degrees C. When the plants were returned to 22 degrees C, the expression of CCT also decreased to the original level.
Amino Acid Sequence↗